Iron Status of Newborns in Maternal Inflammation Status

Differences

Qodri Santosa

, Alfi Muntafiah

, and Lantip Rujito

Department of Child Health, Faculty of Medicine, Universitas Jenderal Soedirman, Purwokerto, Indonesia

Department of Biochemistry, Faculty of Medicine, Universitas Jenderal Soedirman, Purwokerto, Indonesia

Department of Molecular Biology, Faculty of Medicine, Universitas Jenderal Soedirman, Purwokerto, Indonesia

Keywords: inflammation, pregnancy, IL-6, CRP, iron status, ferritin, newborn

Abstract: The human nervous system develops rapidly during the last pregnancy period and the beginning of human

life, requiring much iron. Inflammation during pregnancy may interfere with materno-fetal iron transfer. The

study aimed to compare the newborn iron status levels in maternal inflammation status differences. A cross-

sectional study was conducted with subjects of 84 clinically healthy newborns. We used C-reactive protein

(CRP) and interleukin-6 (IL-6) as parameters of maternal inflammation. Maternal IL-6 was classified into two

test groups based on quartile 1 (Q1) and quartile 2-4 (Q2-4), while CRP in the positive and negative groups.

Statistical analysis used a t-test independent or Mann-Whitney test, with 95% confidence intervals and a

significance limit at p <0.05. All newborns and their mothers were in healthy condition. Ferritin newborns'

levels were higher in the positive than negative CRP group (450.6 ± 194.86 vs. 365.1 ± 212.91, with p = 0.02).

Ferritin newborns were also higher in the maternal IL-6 Q2-4 group than in Q1, at levels 299.03 ± 154.98 vs.

492.35 ± 276.25, with p = 0.003. The study concluded that newborns' serum ferritin levels are higher in the

maternal with CRP-positive and higher IL-6 groups. We should be careful in interpreting the elevated serum

ferritin because it is also an acute-phase reactant.

1 INTRODUCTION

Iron sufficiency during late pregnancy and early

human life is essential for the nervous system's rapid

growth (Collard, 2009). Cellular respiration in the

hippocampus and frontal cortex, neurotransmitter

concentrations, fatty acid profiles, and myelination

will be disrupted if an iron deficiency occurs during

this period, potentially disrupting growth and

development (Georgieff, 2007).

An iron status assessment is essential, but no

single laboratory examination can determine the

diagnosis in all compartments, among red blood cells,

transport, functional, and storage (Wu, 2002). Human

iron stores in the body exist primarily in the form of

ferritin. Declining (low) serum ferritin levels reflect

depleted iron stores. However, ferritin is an acute-

phase reactant whereby concentrations increase

during inflammation and no longer reflect the iron

https://orcid.org/0000-0001-7712-2549

https://orcid.org/0000-0002-1424-6111

https://orcid.org/0000-0001-6595-3265

store's size. Interpretation of average or high serum

ferritin values is difficult in areas of widespread

infection or inflammation. Without inflammation or

liver disease, increased serum ferritin concentrations

indicate iron overload (WHO, 2011).

The inflammatory process is generally

characterized by an increase in pro-inflammatory

cytokines and acute-phase reactants levels.

Interleukin-6 (IL-6), a pro-inflammatory cytokine,

and C-reactive protein (CRP) are the primary

mediators of the host response to inflammation, and

both are also early markers of the acute-phase

response (Sorokin et al., 2010). High levels of IL-6 in

pregnancy can induce hepcidin transcription.

Interleukin-6 - hepcidin axis is responsible for

hypoferremia in pregnant women with excessive

inflammation (Zhang & Enns, 2009; Wrighting &

Andrews, 2006), then interferes with a materno-fetal

194

Santosa, Q., Muntaﬁah, A. and Rujito, L.

Iron Status of Newborns in Maternal Inﬂammation Status Differences.

DOI: 10.5220/0010490001940201

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 194-201

ISBN: 978-989-758-499-2

iron transfer (Nemeth et al., 2004), and may affect

neonatal iron status (Yanoff et al., 2007).

Mild acute inflammation did not increase serum

hepcidin in pregnant women with iron deficiency

anemia. Even Abioye et al. confirmed that anemia of

inflammation during human pregnancy did not affect

newborn iron endowment (Abioye et al., 2018). The

underlying mechanisms are still being debated so that

during pregnancy, it seems unclear how the

difference in newborn iron status between maternal

inflammation status differences.

This study aimed to compare the newborn iron

status in maternal inflammation status differences,

using maternal IL-6 and CRP inflammation

parameters.

2 MATERIAL AND METHODS

Our study was part of comprehensive research that

assessed various factors associated with neonates'

iron status. A cross-sectional study was conducted in

Purbalingga Regency, Central Java, Indonesia, in

three hospitals, with 84 newborns, from September to

November 2015. The inclusion criteria for newborns

were born spontaneously, from single and term

pregnancy, normal birth weight (≥2.500 to <4.000

grams), with an Apgar score ≥of 7 in the first minute,

and not suffer from significant congenital

abnormalities. We excluded newborns subjects if they

were suffering from severe illness and hematologic-

oncological disease, and the mother had a postpartum

hemorrhage. The Health and Medical Research Ethics

Commission of the Faculty of Medicine, Diponegoro

University/Dr. Kariadi Hospital Semarang provided

ethical approval with No.48/EC/FKRSDK/2015. The

father or mother of the newborn subject signed the

written informed consent before joining the research.

We used CRP and IL-6 as parameters of maternal

inflammation, using maternal venous blood samples.

Maternal IL-6 was classified into two test groups

based on quartile 1 (Q1) and quartile 2-4 (Q2-4),

while CRP in the positive and negative groups.

Newborn iron status parameters included red blood

cell (RBC) count, hemoglobin (Hb), hematocrit (Ht),

and hepcidin using blood samples taken from

umbilical cord blood. In contrast, serum iron (SI) and

serum ferritin (SF) were taken from newborns'

venous blood.

Maternal venous blood samples were taken when

the mother was admitted to the hospital for delivery.

The blood samplings from the umbilical cord blood

were collected immediately after the placenta was

born, whereas the newborn's vein was performed

directly after the baby was born. Parameters of RBC

count, Hb, and Ht of newborns were checked using

Sysmex XN-1000, while hepcidin using the ELISA

method. SI was tested using the IRON Flex® reagent

cartridge, Cat. No. DF85, while SF and maternal IL-

6 using the chemiluminescence immunoassay

(ECLIA) method. Maternal CRP was performed

using the C-Reactive Protein Extended Range

(RCRP) method used on the Dimension® clinical

chemistry.

The statistical analysis to compare newborn

iron status between maternal inflammation status

differences was tested with the independent t-test or

Mann-Whitney test. In groups (positive and

negative), maternal CRP, hepcidin variables were

analyzed using the Mann-Whitney test, while other

variables used the independent t-test. In the two

maternal IL-6 quartile groups (Q1 and Q2-4), variable

RBC, hematocrit, and hepcidin variables were

analyzed using the Mann-Whitney test, while other

variables were tested using an independent t-test. The

statistical test used 95% confidence intervals, with a

limit of significance at p <0.05.

3 RESULTS

A total of 84 newborns participated in our cross-

sectional study. We interviewed as many as 108

pregnant women/parents of prospective subjects in

the initial process. Seven pregnant women refused

because they were afraid or worried about the blood

collection process. Two babies with clinical features

of Down's syndrome, four babies born with

respiratory problems, and 11 babies failed blood

sampling or laboratory techniques, so they could not

continue the study process.

All newborn subjects were at term babies,

born spontaneously, from singleton pregnancies,

Apgar scores ≥ seven at the first minute, average birth

weight (≥ 2,500 to <4,000 grams), and not suffering

from significant congenital abnormalities. The CRP

of all newborn subjects was negative. (Table 1). Table

2 shows that all maternal subjects were pregnant at

term, did not suffer from diabetes mellitus, pre-

eclampsia/eclampsia, and antepartum hemorrhage,

came from Javanese, and with Hb >8 g/dL.

The results showed that hematocrit levels, SF,

and hepcidin newborns in the maternal CRP group

had abnormal data distribution. The hepcidin variable

was still not standard after being transformed, so it

was analyzed using the Mann-Whitney test, while

other variables used the independent t-test. (Table 3)

Iron Status of Newborns in Maternal Inﬂammation Status Differences

195

Table 1. Characteristics of newborn

Characteristics of newborn Value

Sex (gender):

- Male, n (%)

- Female, n (%)

38 (45.2)

46 (54.8)

Gestation, week [median

(ran

39.22

(37

–

41)

Apgar score (AS)

- 1 min, [median (ran

e) 8.04 (7

–

- 5 min, [median (ran

e) 9 (8

–

10)

Heart rate,

eats/min [median (ran

129.88

(110

–

148)

Birth weight,

ram [median (ran

3190.06

(2600

–

3900)

CRP:

- Positive, n (%)

ative, n (%)

84 (100)

0 (0)

Table 2. Characteristics of the mother

Characteristics of mother Value

Age of mother, year (𝑥 ± SD) 27.43 ± 5.38

Gravida:

- Gravida ≤ 2, n (%)

- Gravida ≥ 3, n (%)

68 (81.0)

16 (19.0)

Education levels:

- > Senior High School, (%)

- ≤ Senior Hi

h School, (%)

20 (23.8)

64 (76.2)

Systolic, mmHg (𝑥±SD)

119.85 ± 9.19

Diastolic, mmHg (𝑥±SD) 73.33 ± 6.47

Fe tablet, n (%) 84 (100)

Ante-natal care ≥ fou

times 84 (100)

Smoking during pregnancy:

- Yes, (%)

o, (%)

1 (1.2)

83 (98.8)

Table 3. Iron Status Parameters based on Maternal CRP Groups

Iron Status Newborns Parameters

Maternal CRP Groups

CRP positive

(n=48)

CRP negative

(n=36)

RBC (umbilical cord), 10

/mm

(𝑥±SD) 4.2±0.44 4.3±0.46 0.209

Hb (umbilical cord), g/dL (𝑥±SD)

15.2±1.47

15.2±1.49

0.857

Ht (umbilical cord), % (𝑥±SD) 45.0±5.12 44.9±4.98 0.986

Serum Iron, μg/dL (𝑥±SB) 114.3±51.30 111.3±54.96 0.799

Serum Ferritin ng/

L (𝑥±SD)

450.6±194.86 365.1±212.91 0.023

Hepcidin (umbilical cord), ng/mL

(𝑥

±SD)

[median (min-max)]

4.2±1.62

4.8(1.66-6.90)

3.8±1.73

3.3(1.58-6.85)

0.426

Remarks: a t-test independent; b, Mann-Whitney; *, ferritin, n=45

The results showed that SF newborn levels were

higher in the CRP positive mothers group than the

opposing group, with a mean of 450.6 ± 194.86 vs.

365.1 ± 212.91 ng/mL with p = 0.023. Other

parameters of iron status for newborns were not

significantly different in these maternal CRP groups.

We divided newborns subjects into the two quartile

groups of maternal IL-6 (Q1 and Q2-4). Parameters

RBC, hematocrit, and hepcidin levels have abnormal

data distribution. After transforming the data, the data

distribution of hematocrit and hepcidin were not

expected, so they were analyzed using the Mann-

Whitney test. Meanwhile, other variables were tested

using an independent t-test. Table 4 shows that the

mean SF newborns in the quartile group (Q1 vs. Q2-

4) were higher in the maternal IL-6 group Q2-4, with

a mean of 299.03 ± 154.98 v.s 492.35 ± 276.25 ng/mL

and statistically significant with p = 0.003. In Table

5, we divided newborn hepcidin and SF into maternal

IL-6 gradations Q1, Q2-3, and Q4. Among the

maternal IL-6 quartile group, we found that the

median hepcidin cord blood was not different (p:

0,610), while the mean of newborn SF was

significantly different (p: 0.006). However, by post

hoc of LSD analysis, we only found differences in SF

newborns' standard in the IL-6 Q1 vs. Q2-3 (p:

0.002). Meanwhile, the newborn SF levels in the IL-

6 maternal Q1 group were not different from the Q4

group (p: 0.068). Likewise, the mean SF newborns at

Q2-3 and Q4 did not differ (p: 0.267).

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

196

Table 4. Iron status parameters based on maternal IL-6 quartile (Q1 and Q2-4) groups

Iron Status Newborns Parameters

Maternal IL-6 Quartile Groups

Q1 (n=21)

Q2-4 (n=63)

RBC (umbilical cord), 10

/mm

(𝑥

±SD)

4.3±0.47 4.2±0.45 0.432

Hb (umbilical cord), g/dL

(𝑥

±SD)

15.4±1.80

15.1±1.35

0.358

Ht (umbilical cord), % (𝑥±SD)

[median (min-max)]

45.7±5.88

44.5(38.10-

59.70)

44.7±4.74

44.3(34.80-

56.90)

0.877

Serum Iron, μg/dL (𝑥±SB) 121.7±50.34 110.1±53.40 0.386

Serum Ferritin ng/

L (𝑥±SD)

299.03±154.98 492.35±276.25 0.003

Hepcidin (umbilical cord),

ng/mL (𝑥

±SD)

[median (min-max)]

4.2±1.75

3.6(1.58-6.85)

4.0±1.65

3.9(1.66-6.90)

0.345

Remarks: a t-test independent; b, Mann-Whitney test; *, ferritin neonatal (n=61)

Table 5. Serum ferritin and hepcidin of newborn based on maternal IL-6 quartile (Q1, Q2-3, and Q4) groups

Newborns Parameters

Maternal IL-6 Quartile Groups

Quartile 1

(n=21)

Quartile 2-3

(n=42)

Quartile 4

(n=21)

Hepsidin cord blood,

[median (min-max)]

3.6 (1.58-

6.85)

4.4 (1.66-

6.90)

3.9 (1.83-

5.89)

0.610

Serum ferritin, ng/mL,

(𝑥

±SB)

299.0 ±

154.98

472.3 ±

206.75

412.3 ±

210.61

0.006

Remarks:

Statistical tests used 95% confidence intervals (𝑥

±SB), mean ± standard deviations; a one-way Anova test; Post hoc analysis

of LSD: IL-6 Mother quartile I vs. II-III p = 0.002; I vs. IV p = 0.068; II-III and IV p = 0.267

4 DISCUSSION

The study aimed to compare the newborn iron status

levels in maternal inflammation status differences.

The newborns' iron status using the RBC count, Hb,

Ht, SI, and hepcidin did not differ between the

maternal CRP group (positive vs. negative) and the

IL-6 maternal quartile group (Q1 vs. Q2-4). In

contrast above, the mean SF newborn was

significantly higher in the CRP positive group.

Likewise, the mean SF newborn was higher in the

maternal IL-6 Q2-4 group (inflammatory mothers), p

<0.05. However, after dividing the maternal IL-6 into

Q1, Q2-3, and Q4, the newborn SF levels in the IL-6

Q4 group tended to decrease compared to Q2-3,

although the two groups did not differ significantly.

These results indicate that iron status was

generally unaffected. Still, SF newborns as a

parameter of iron storage will increase or be higher in

newborns born to mothers with positive CRP and

more elevated IL-6 (inflammatory mothers). We

assume that maternal inflammatory status in the last

trimester of pregnancy tends to increase the iron

stores (SF) of babies born under normal pregnancy

conditions. We considered that the maternal

inflammatory disease is a "physiological strategy" to

increase iron storage (SF levels) of the fetus for the

third trimesters' rapid growth.

Research on inflammation in pregnancy (such as

pregnancy with obesity) has different effects. Dao et

al. found no statistically significant differences in

CRP, IL-6, or hepcidin levels in cord blood between

the obese and non-obese maternal groups (Dao et al.,

2013). Still, serum iron and transferrin saturation in

cord blood were lower in neonates born to obese

women than those of average weight. Furthermore,

Cao et al. also concluded that the prepregnancy body

mass index (BMI) has no negative impact on maternal

or neonatal iron status (Cao et al., 2016). Jones et al.

(2016) reported that maternal obesity during

pregnancy is negatively associated with maternal and

neonatal iron status (Jones et al., 2016). Research in

316 newborns said that compared to non-obese

pregnant women (BMI <30 kg/m2), obese women

Iron Status of Newborns in Maternal Inﬂammation Status Differences

197

delivered offspring with lower iron status, as assessed

using SF and zinc protoporphyrin/heme (Phillips et

al., 2014).

Inflammation is the necessary process as a

response to injury and also central to reproductive

success. Such as ovulation, menstruation,

implantation, and parturition are all inflammatory

processes. A physiologic systemic inflammatory

response also characterizes pregnancy (Romero et al.,

2007). Concentrations of CRP and IL-6 in obese

women compared to normal-weight women indicated

an inflammatory response (Buss et al., 2012). CRP

level has been reported to be elevated in pregnant

women without pregnancy complications than in non-

pregnant women (Fink et al., 2019; Watts et al.,

1991). Reproductive success appears to be influenced

by cytokine activity's strict regulation (Austgulen et

al., 1994). So, if not exaggerated/not excessive,

inflammation has essential roles in reproductive

physiology.

Another review of the inflammatory process, in

which chronic and excessive inflammation of

pregnancy can lead to poor pregnancy outcomes.

Generally, research on IL-6 in pregnancy has been

associated with poor outcomes in mothers and their

babies. IL-6 has been implicated as a mediating factor

in maternal inflammation processes to alterations in

fetal brain development (Buss et al., 2012; Rudolph

et al., 2018; Estes and McAllister, 2016).

The main factor responsible for altered iron

metabolism in inflammatory conditions is hepcidin

(Wessling-Resnick, 2010). Hepcidin regulated iron

homeostasis by controls iron absorption and recycling

(Ganz, 2013).

Transcription of hepcidin is induced

when systemic iron levels are high and down-

regulates its receptor, ferroportin (FPN), preventing

iron export to blood plasma (Ganz, 2013). The

abnormality of raised hepcidin causes intracellular

sequestration and decreased intestinal iron absorption

due to the downregulation of FPN expression in

macrophages and enterocytes (Cherayil, 2015).

Furthermore, changes in hepcidin levels can rapidly

modulate and control plasma iron concentrations.

Commonly, in non-pregnant obese women,

hepcidin is up-regulated (Tussing-Humphreys et al.,

2012), otherwise during a healthy pregnancy,

hepcidin is reduced and enabling increased materno-

fetal iron transfer (Fisher & Nemeth, 2017). Maternal

hepcidin is suppressed during the second and third

trimesters, which increases iron availability for

materno-fetal transfer (Fisher & Nemeth, 2017). The

mechanism of maternal hepcidin suppression is

unclear (Sangkhae et al., 2020). The interpretation of

hepcidin levels, such as ferritin, should also be

considered concurrently with inflammation markers

(Sanni et al., 2020).

The inflammatory markers of CRP and IL-6 have

long been known. As a pro-inflammatory cytokine,

IL-6 is frequently elevated in obese pregnant women.

It has been shown to induce hepcidin expression, a

negative regulator of intestinal iron absorption,

macrophage iron efflux, and hepatic iron stores (Ganz

& Nemeth, 2006). Inflammation, such as obesity in

pregnant women, may lead to hepcidin excess and

decreased iron transfer to the fetus (Flynn et al.,

2018), affecting newborn iron status.

In low-grade inflammation in non-pregnant

women, obesity is associated with increased hepcidin,

induced iron sequestration, and decreased circulating

iron (Tussing-Humphreys et al., 2012). The CRP and

IL-6 were more remarkable in obese than normal-

weight pregnant women (Fisher & Nemeth, 2017),

and inflammatory conditions in pregnancy are lower

and more visualized in obese pregnancies (Dosch et

al., 2016). However, Flynn et al. found no

relationship between CRP or IL-6 and hepcidin in

obese or normal-weight women. It might indicate that

the association between inflammatory mediators and

hepcidin is not extant in pregnancy (Fisher and

Nemeth, 2017). Other pathways may play an essential

iron regulatory role in pregnancy.

Why does maternal inflammatory condition

increase in SF newborns (iron stores) while all

newborn subjects with CRP are negative? A recent

study confirmed that mild acute inflammation did not

increase serum hepcidin in women with IDA,

suggesting that low iron status and erythropoiesis

drive offset the inflammatory stimulus on hepcidin

expression. In non-anemic women, inflammation

increased serum hepcidin and produced mild

hypoferremia. However, it did not reduce dietary iron

absorption, suggesting that iron-recycling

macrophages are more sensitive than the enterocyte

high serum hepcidin during inflammation (Stoffel et

al., 2019). Abioye et al. confirmed that anemia of

inflammation during human pregnancy did not affect

newborn iron endowment (Abioye et al., 2018).

Previous concepts still understand that cytokines

(e.g., IL-6) can cross the placenta when the placental

barrier was damaged. An animal experiment by

Dahlgren J et al. proved that maternal IL-6 could

cross the placental border to the fetus, both in a

condition where the placental barrier is impaired or

normal (Dahlgren et al., 2006). In previous research,

Zaretsky et al. confirmed that fetal IL-6 could also

penetrate the placenta into the maternal circulation

(Zaretsky et al., 2004). So, IL-6 can pass bidirectional

transfer from maternal to fetus and vice versa.

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

198

Maternal IL-6 passes to the fetus, and subsequently,

IL-6 in the fetus can affect iron status.

Our data (Table 5) showed, in maternal IL-6

gradations Q1, Q2-3, and Q4, we found that the mean

of newborn SF was significantly different among

those groups. The Post Hoc of LSD analysis stated

that SF newborns' standard was higher in the IL-6

maternal Q2-3 (middle quartile) group than in the Q1

(lowest quartile) group with p: 0.002. We also noted

that the newborn SF levels in the IL-6 Q4 (highest

quartile) group were not different from the Q1 and

Q2-3 groups. The hepcidin and SF newborn values

increased IL-6 maternal Q1 to Q2-3, then decreased

in the IL-6 Q4 group. These results may indicate an

inverted U-shaped association between IL-6 maternal

and neonatal iron status (SF and hepcidin).

Maternal iron status (including serum ferritin) has

a U-shaped association with adverse pregnancy

outcomes (Dewey & Oaks, 2017). We must be

careful because SF is also an acute-phase reactant.

However, elevated ferritin is a marker of increased

iron stores and inflammation, and the specific

contribution of excess iron has not been resolved. It

is poorly understood how to regulate iron homeostasis

between maternal and fetal during pregnancy,

including maternal, placental, and fetal signals

(Sangkhae et al., 2020). Like ferritin, IL-6 maternal,

as an acute-phase response, so we must be careful to

interpret the meaning of increased SF in newborns.

The implication of this study, because there is an

indication of an inverted U-shaped association

between maternal inflammation (levels of maternal

IL-6) and neonatal iron status. Hence less or

excessive inflammation may decrease the iron status

of newborns. We must be careful to interpret the

newborn SF level because it is also an acute reaction

protein.

5 CONCLUSION

Our study compared neonate iron status levels in

maternal inflammation status differences. Our

findings indicated that inflammation is the necessary

process for reproductive success. We conclude that

(not excessive) inflammation in pregnancy does not

affect iron status (based on RBC count, Hb, Ht, SI,

hepcidin parameters) but increases the SF (iron

storage) of the newborns. The SF levels of newborns

are higher in the maternal with CRP-positive and

higher IL-6 groups. There is an indication of an

inverted U-shaped association between maternal

inflammation and neonatal iron status. Hence less or

excessive inflammation during pregnancy may

decrease the iron status of newborns. We must be

careful to interpret the newborn SF level because it is

also an acute reaction protein. This study's limitation

could not conclude a cause and effect between

maternal inflammation and the iron status of

newborns because it is only an observational study.

Future studies need to involve broader factors,

especially IL-6, hepcidin, and other variables

affecting neonate iron status in maternal, placenta,

and cord blood. It is necessary to carry out research

that can describe how orchestral iron metabolism in

the fetus.

ACKNOWLEDGMENTS

Our gratitude goes to all parties involved in the

research, from Ummu Hani Hospital, Harapan Ibu

Hospital, and Panti Nugroho Hospital, Purbalingga.

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